CN103153989A - Cathepsin s inhibitor compounds - Google Patents
Cathepsin s inhibitor compounds Download PDFInfo
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- CN103153989A CN103153989A CN2011800507006A CN201180050700A CN103153989A CN 103153989 A CN103153989 A CN 103153989A CN 2011800507006 A CN2011800507006 A CN 2011800507006A CN 201180050700 A CN201180050700 A CN 201180050700A CN 103153989 A CN103153989 A CN 103153989A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
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- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof. Also, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier. The present invention further provides methods for treating abdominal aortic aneurysm, plaque instability, atherosclerosis, or autoimmune disorders such as rheumatoid arthritis, psoriasis, and lupus. The method comprises administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
Description
The present invention relates to the inhibitor compound of proteolytic ferment cathepsin S, and the methods for the treatment of that comprises the described compound of administration.The present invention is specifically related to steric isomer.More specifically, the invention provides have two chiral centres effectively, selectivity and reversible steric isomer inhibitor compound.
Cathepsin S is the lysosome L-Cysteine HCL Anhydrous.It belongs to larger tissue protein enzyme family, comprises L, B, K, V and F.Selectivity to cathepsin S can be avoided undesirable consequence, such as side effect.Cathepsin S is produced by inflammatory cell such as dendritic cell, bone-marrow-derived lymphocyte and scavenger cell.Its participate in comprising some patient's condition of atherosclerosis and abdominal aortic aneurysm (AAA) pathology (
j. Clin. Invest.1999,104(9), 1191-1197) (
am. J. Path.2007,170(3), 809-817).
The arterial wall endotheliocyte can be because causing some factor malfunctions of Mottling formation and growth in arterial wall, described factor comprise elevated cholesterol, stress, general health and heredity.This malfunction causes producing and raise inflammatory cell by blood, and described inflammatory cell sees through arterial wall in case stop loss wound.These inflammatory cells finally produce cathepsin S.The effect of cathepsin S is that the degradation of cell extracellular matrix protein is such as the elastin and the collagen that form arterial wall.Carry out repairing impaired arterial wall although reinvent in the extracellular of cell, if too much proteolysis substrate degradation occurs with the sediment-filled phase ratio of stromatin, imbalance may cause the unstable of formed patch in arterial wall.Excessive patch unstable (plaque instability) can cause plaque rupture, and may cause the event relevant to thrombosis.Therefore, inhibiting cathepsin S provides treatment atherosclerotic means.
Sometimes, the extracellular matrix of aorta abdominalis also can, because excessive degradation weakens, cause being called as the patient's condition of AAA.At present, AAA ranked tenth position in the reason that causes deaths in men more than 55 years old.There is no the known pharmacological agent of getting permission to point to AAA.Inhibiting cathepsin S provides the alternate item of seeking to solve this unsatisfied medical requirement.
In addition, cathepsin S is got involved by transmission in the cell when immunne response starts, and it participates in autoimmune disorder, autoimmune disorder can comprise rheumatoid arthritis, lupus and psoriasis (
immunity, 2001,15,909-919) (
eur. J. Immunol.2005,35,2552-2562).Particularly, the Iip10(p10 in cathepsin S cracking bone-marrow-derived lymphocyte and dendritic cell), the Ii-peptide of generation CLIP(II class association).This makes for example loading of autoantigen and presenting of follow-up II class ajor histocompatibility mixture (MHC) molecule of peptide fragment on the cell surface of antigen presenting cell.Thus, the activation of immature T cell causes producing autoimmune response subsequently.Therefore, the inhibition blocking-up p10 processing of cathepsin S and the surface of T cell antigen are presented, the means for the treatment of autoimmunization associated conditions such as rheumatoid arthritis, psoriasis and lupus are provided thus.
Accordingly, the invention provides formula (I) compound:
Or its pharmacologically acceptable salt,
Wherein Z is-CH
2-,-CH
2cH
2-,-OCH
2-,-CH
2cH
2cH
2-or-OCH
2cH
2-;
R
1h, F or Cl;
R
2h, methyl, ethyl, propyl group or sec.-propyl.
One aspect of the present invention provides pharmaceutical composition, and this pharmaceutical composition comprises formula (I) compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable diluent or carrier.
Another aspect of the present invention provides by the compounds of this invention of drug treatment significant quantity or its pharmacologically acceptable salt or comprises the compounds of this invention or method that the pharmaceutical composition of its pharmacologically acceptable salt is treated AAA.Of the present inventionly the compounds of this invention or its pharmacologically acceptable salt by the drug treatment significant quantity is provided on the one hand again or comprises the compounds of this invention or method that the pharmaceutical composition of its pharmacologically acceptable salt is treated Mammals AAA, described Mammals is such as being people, dog, cat, ox, horse, sheep or monkey.Of the present inventionly the compounds of this invention or its pharmacologically acceptable salt by the drug treatment significant quantity is provided on the one hand again or comprises the compounds of this invention or method that the pharmaceutical composition of its pharmacologically acceptable salt is treated people AAA, about 3 centimetres but be less than approximately 5 centimetres and do not need to repair in the upper or blood vessel of operation than normal diameter of described people's aorta diameters.Of the present inventionly the compounds of this invention or its pharmacologically acceptable salt by the drug treatment significant quantity is provided on the one hand again or comprises the compounds of this invention or method that the pharmaceutical composition of its pharmacologically acceptable salt is treated people AAA, described people's aorta diameter be greater than approximately 5 centimetres but operation is upper or blood vessel in reparation be not the treatment alternate item.
Another aspect of the present invention provides by the compounds of this invention of drug treatment significant quantity or its pharmacologically acceptable salt or comprises the compounds of this invention or the pharmaceutical composition of its pharmacologically acceptable salt is treated the instable method of Mammals patch, and described Mammals is such as being people, dog, cat, ox, horse, sheep or monkey.
Of the present inventionly the compounds of this invention or its pharmacologically acceptable salt by the drug treatment significant quantity is provided on the one hand again or comprises the compounds of this invention or the pharmaceutical composition of its pharmacologically acceptable salt is treated the atherosclerotic method of Mammals, described Mammals is such as being people, dog, cat, ox, horse, sheep or monkey.
Of the present inventionly the compounds of this invention or its pharmacologically acceptable salt by the drug treatment significant quantity is provided on the one hand again or comprises the compounds of this invention or the pharmaceutical composition of its pharmacologically acceptable salt is treated the method that needs its Mammals autoimmune disorder, described Mammals is such as being people, dog, cat, ox, horse, sheep or monkey.Of the present inventionly the compounds of this invention or its pharmacologically acceptable salt by the drug treatment significant quantity is provided on the one hand again or comprises the compounds of this invention or the pharmaceutical composition of its pharmacologically acceptable salt is treated the method for people's psoriasis, rheumatoid arthritis or lupus.
The compound or pharmaceutically acceptable salt thereof that is provided on the one hand again treatment of the present invention.Another aspect of the present invention is provided for treating the compound or pharmaceutically acceptable salt thereof of abdominal aortic aneurysm, patch unstable, atherosclerosis or autoimmune disorder such as rheumatoid arthritis, psoriasis and lupus.Of the present invention is the purposes of compound or pharmaceutically acceptable salt thereof for the preparation of the medicine for the treatment of abdominal aortic aneurysm, patch unstable, atherosclerosis or autoimmune disorder such as rheumatoid arthritis, psoriasis and lupus more on the one hand.
Another aspect of the present invention provides pharmaceutical composition, and this pharmaceutical composition comprises the compounds of this invention or its pharmacologically acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle and chooses any one kind of them or multiple other therapeutical agent.
The compounds of this invention or its pharmacologically acceptable salt that is provided for treating on the one hand again abdominal aortic aneurysm, patch unstable, atherosclerosis, rheumatoid arthritis, psoriasis and lupus of the present invention.
The compounds of this invention or its pharmacologically acceptable salt purposes for the preparation of the medicine for the treatment of abdominal aortic aneurysm, patch unstable, atherosclerosis, rheumatoid arthritis, psoriasis and lupus that provides on the one hand more of the present invention.
Inhibitor compound and comprise that the embodiment of the methods for the treatment of of the described inhibitor compound of administration comprises above-mentioned R in the present invention
1, R
2any combination with Z.Particularly, embodiment of the present invention relate to formula (I) compound or pharmaceutically acceptable salt thereof, wherein R
1h or F.More specifically, embodiment of the present invention relate to formula (I) compound or pharmaceutically acceptable salt thereof, wherein R
1f.
Another embodiment of the present invention is formula (I) compound or pharmaceutically acceptable salt thereof, wherein R
2methyl or ethyl.Particularly, embodiment of the present invention are formula (I) compound or pharmaceutically acceptable salt thereof, wherein R
2it is methyl.
An embodiment more of the present invention relates to formula (I) compound or pharmaceutically acceptable salt thereof, and wherein Z is-CH
2-,-CH
2cH
2-,-OCH
2-,-CH
2cH
2cH
2-or-OCH
2cH
2-.Particularly, embodiment of the present invention are formula (I) compound or pharmaceutically acceptable salt thereofs, and wherein Z is-CH
2cH
2-or-OCH
2-.Further embodiment of the present invention is by R wherein
1h or F, R
2be methyl or ethyl, and Z is-CH
2cH
2-or-OCH
2-combination form.
Preferred compound example of the present invention is as follows:
The N-methyl carbamic acid [(3R, 4S)-4-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-3-yl] ester,
The N-methyl carbamic acid [(1S, 2S)-1-[(4-fluoro benzoyl) amino]-7-[4-(trimethylene oxide-3-yl) piperazine-1-yl] tetralin-2-yl] ester,
The N-methyl carbamic acid [(1S, 2S)-1-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] indane-2-yl] ester,
The N-methyl carbamic acid [(8S, 9S)-9-[(4-fluoro benzoyl) amino]-2-[4-(trimethylene oxide-3-yl) piperazine-1-yl]-6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-8-yl] ester, and
The N-methyl carbamic acid [(4S, 5S)-5-[(4-fluoro benzoyl) amino]-7-[4-(trimethylene oxide-3-yl) piperazine-1-yl]-2,3,4,5-tetrahydrochysene-1-benzo oxa-
-4-yl] ester.
Preferred the compounds of this invention is:
The N-methyl carbamic acid [(3R, 4S)-4-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-3-yl] ester,
The N-methyl carbamic acid [(1S, 2S)-1-[(4-fluoro benzoyl) amino]-7-[4-(trimethylene oxide-3-yl) piperazine-1-yl] tetralin-2-yl] ester, and
The N-methyl carbamic acid [(8S, 9S)-9-[(4-fluoro benzoyl) amino]-2-[4-(trimethylene oxide-3-yl) piperazine-1-yl]-6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-8-yl] ester.
Most preferred the compounds of this invention is:
The N-methyl carbamic acid [(3R, 4S)-4-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-3-yl] ester.
Otherwise indicated, above with the following term of each place use of specification sheets of the present invention, there is following implication:
Term used herein " abdominal aortic aneurysm " (or " AAA ") means the aortal localization expansion in Mammals midfield or bulge, and it causes that the size of at least one section aorta abdominalis surpasses other and is considered to the size of standard state.Aorta abdominalis can utilize any measurement size measure and compare, and includes but not limited to chamber diameter, cavity perimeter and cavity area.Measure and diagnostic means can be by carrying out with ultrasonic, CT scan or other imaging technique.For example, when aorta diameter be greater than its normal diameter approximately 3 centimetres the time people AAA appears.Yet, if aorta diameter is greater than approximately 5 centimetres, for avoiding breaking and possible mortality, repairing (support or transplanting) in immediate surgery or blood vessel is standard care.Yet if can not get such treatment, or, because of any reason for example age rather than alternate item, this crowd also can utilize the present invention to be treated.
The patient's condition that term used herein " needs it " and meant or is diagnosed as needs and treats, for example atherosclerosis, AAA, autoimmune disorder such as psoriasis, lupus or rheumatoid arthritis.
Term used herein " Mammals " means people or non-human mammal such as dog, cat, ox, horse, sheep or monkey.
Term " its pharmacologically acceptable salt " refers to the salt of the compounds of this invention.Example and their preparation method are the known knowledge of those skilled in the art.Referring to for example, Stahl etc.
," Handbook of Pharmaceutical Salts:Properties, Selection and Use ", VCHA/Wiley-VCH, 2002.
Amount or the dosage of the composition that term " treatment significant quantity " refers to formula (I) compound in order to realize treatment or comprises formula (I) compound.The attending doctor, as class those skilled in the art, body weight through considering some factors such as the patient known to those skilled in the art, height, age, general health situation, patient's condition severity, administering mode, therapeutic regimen etc., can easily determine and treat significant quantity.
Term used herein " treatment " means to make the speed of morbid state or progress to slow down.It also can comprise the termination morbid state.Term can not only comprise the termination disease further, and comprises and alleviate any morbid state occurred.For example, with regard to AAA, term " treatment " can mean to slow down the spreading rate of abdominal aortic aneurysm.It also can comprise the expansion that stops abdominal aortic aneurysm.In addition, it can comprise and alleviates any expansion occurred.
Sign "
" refer to the key that protrudes from forward page plane.
Sign "
" refer to the key that protrudes from backward page plane.
Term " OCH in " Z " definition
2-" and " OCH
2cH
2-" be interpreted as meaning oxygen and benzo ring (benzo ring) adjacency condensed.
The compounds of this invention preferably is formulated as pharmaceutical composition.Example and their preparation method are the known knowledge of those skilled in the art.Referring to for example, Remington:The Science and Practice of Pharmacy(A. Gennaro etc. writes, and the 19th edition, Mack Publishing Co., 1995).
Can be through various programs known in the art, and the program described in following scheme, preparation and embodiment is come preparation I compound or its salt.The concrete synthesis step of each route can combine in a different manner, with preparation I compound or its pharmacologically acceptable salt.
The further example the present invention of following preparation and embodiment, and represent that as above the typical case of formula (I) compound (comprising any new compound) of general introduction is synthetic.Reagent and starting raw material are that those of ordinary skills are easy to obtain, and maybe can be easy to by those of ordinary skills synthetic.Should be understood that preparation and embodiment as example and non-limiting the elaboration, those of ordinary skills can carry out various improvement.
Can determine R or the S configuration of the compounds of this invention such as X-ray analysis with the dependency of chirality HPLC retention time via standard technique.The name of following preparation and embodiment generally adopts the IUPAC name feature in Symyx Isentris 3.2.3 version to complete.
As used herein, following term has specified implication: " AcOH " refers to acetic acid; " BCA " refers to dihomocinchonine acid (bicinchoninic acid); " b.i.d. " refers to twice of every day; " salt solution " refers to the saturated NaCl aqueous solution; " cat. " refers to the amount of catalyzer; " CD74 " refers to constant chain (Ii); " CDI " refers to 1,1'-carbonyl dimidazoles; " DMAP " refers to 4-dimethylaminopyridine; " DMSO " refers to methyl-sulphoxide; " DTT " refers to dithiothreitol (DTT); " EDTA " refers to ethylenediamine tetraacetic acid (EDTA); " EtOH " refers to ethanol; " hr. " refers to hour; " IC
50" refer to produce 50% reagent concentration of the issuable maximum inhibited reaction of reagent place, also or the reagent concentration of part 50% displacement of generation and receptors bind; " IMAC " refers to immobilized metal affinity chromatography; " IPA " refers to Virahol; " LC ES/MS " refers to the liquid chromatography electrospray ionization mass spectrum; " MCPBA " refers to metachloroperbenzoic acid; " MeOH " nail alcohol; " min. " refers to minute; " NBS " refers to N-bromosuccinimide; " NMP " refers to the N-crassitude; " N/A " refers to unavailable; " p10 " refers to the fragment of constant chain CD74; " PBS " refers to phosphate buffered saline (PBS); " PWBC " refers to peripheral blood leucocyte; " RFU " refers to relative fluorescence unit; " SFC " refers to supercritical fluid chromatography; " STAB " refers to the triacetoxyl group sodium borohydride; " SDS " refers to sodium lauryl sulphate; " THF " refers to tetrahydrofuran (THF); " t-boc " or " boc " refers to tert-butoxycarbonyl; " Triton X-100 " refers to that polyoxyethylene glycol is to (1,1,3,3-tetramethyl butyl) phenyl ether.
Otherwise indicated, substituting group as previously defined.
Scheme 1
Can carry out according to reaction shown in scheme 1 formation of intermediate (3).
In scheme 1, steps A, process the bromo-2H-chromene of 6-with NBS, to form bromhydrin (1).Preferred condition is to use DMSO/ water solvent mixture, at approximately 0～50 ℃ but more preferably at room temperature.
In step B, process bromhydrin (1) with ammonium hydroxide, so that amino alcohol (2) to be provided.For example, under room temperature to 60 ℃, make bromhydrin react 4-24 hour with ammonium hydroxide in the THF/EtOH solvent mixture.
In scheme 1, step C, racemic amino alcohol is split into to its 3R, 4S and 3S, the 4R enantiomer, to provide chiral amino alcohol (3).Method for splitting is that those skilled in the art are known, comprises the salt crystallization as chiral acid, or through chirality chromatographic separation enantiomer.
The bromo-2H-chromene of 6-is commercially available, or can be through method preparation well known in the art.For example, the bromo-4-chromanone of 6-can be reduced into to alcohol, eliminate and obtain the bromo-2H-chromene of 6-subsequently.
Scheme 2
Described the synthetic of formula (7) intermediate in scheme 2.
In scheme 2, steps A, by the MCPBA oxidation of formula (4) ring-type alkene, obtain formula (5) epoxide.Described reaction is carried out in the biphase mixture such as methylene dichloride and alkali aqueous solution such as sodium bicarbonate aqueous solution at halogenated solvent.Add MCPBA in batches under-10～10 ℃, under agitation make reaction be warmed to room temperature, used time 1-8 hour.If necessary, add extra MCPBA.
In step B, by formula (5) epoxide ammonia treatment, to form formula (6) racemic amino alcohol.Preferred condition is to use sealed vessel, and the sealing container is equipped with inert solvent such as THF, has wherein added ammonia/methyl alcohol.To react heating 1-4 days under 50-100 ℃, add in case of necessity extra ammonia.
In scheme 2, step C, described in previous routes 1, step C, racemic amino alcohol (6) is split to an accepted way of doing sth (7) chiral amino alcohol.For example, the bromo-tetralin of 1-amino-7--2-alcohol (Y=-CH
2-) by being split with (+)-bis--Isosorbide-5-Nitrae-methyl benzoyl-D-tartrate crystallization.Can be by with alkali aqueous solution, processing salt to obtain wherein Y=-CH
2-(1S, 2S)-amino alcohol, thereby obtain free amine.Selectively, racemize material (6) can be taken to the finished product, and separate enantiomer by chiral chromatography.
It will be appreciated by those skilled in the art that and be easy to buy or obtain by the document currently known methods for, formula (4) ring-type alkene.For example, corresponding ketone can be reduced into to alcohol, eliminate and obtain alkene subsequently.
Scheme 3
Can carry out according to reaction shown in scheme 3 formation of intermediate (11).
In scheme 3, steps A, according to for 1R, contained program in the document of 2R enantiomer (US 7,326,731 B2), by by 5% palladium/hydrocarbonize, obtain aminoidan (9) from nitro indane (8).
In step B, utilize the Sandmeyer reaction, make aminoidan (9) be converted into iodo indane (10).Utilize tosic acid and sodium nitrite in aqueous solution, at solvent such as acetonitrile situ, form diazonium salt.Subsequently, process diazonium salt 0.5-6 h with potassium iodide aqueous solution at 0-30 ℃ of temperature, so that iodo indane (10) to be provided.
In step C, acidic conditions such as HCl or trifluoroacetic acid under, the iodo indane (10) of boc protection is transformed into iodo aminoidan (11).The method of introducing and remove nitrogen-protecting group be in the art well-known (referring to for example, Greene and Wuts,
protective Groups in Organic Synthesis, the 3rd edition, John Wiley and Sons, New York, (1999)).Preferred condition is to use the HCl/ dioxane, under 0～25 ℃, and used time 0.5-4 h.
N-[(1S, 2S)-6-amino-2-hydroxyl-indane-1-yl] t-butyl carbamate (8) can make by methods known in the art.For example, can be in six steps by indenes obtain racemize-anti-form-1-amino-6-nitro indane-2-alcohol (
adv. Synth. Catal.2005,
347, 255-265).The racemize material is split to the 1R of be separated into (+)-L-amygdalic acid, 2R and 1S, 2S salt.1S, 2S salt is released to 1S, and 2S-anti-form-1-amino-6-nitro indane-2-alcohol, protected amine subsequently subsequently in the mode of t-butyl carbamate, as analyzed by chirality HPLC, obtain the material that ee is greater than 97%.
Scheme 4
Can carry out the formation of the compounds of this invention of formula I according to the reaction shown in scheme 4.
In scheme 4, steps A, by formula (12) amino alcohol (chirality or racemic) acidylate, obtain formula (13) acid amides.The process for acylating of various use carboxylic acids or acyl chlorides is well-known in the art.Preferred condition is to use suitable Benzoyl chloride, in the solvent mixture of THF and sodium bicarbonate aqueous solution, and at 0-25 ℃ of temperature, used time 1-8 hour.If initial amino alcohol is used with the form of the salt of chiral acid, with enough alkali, generate unhindered amina.
In step B, utilize cupric iodide (I) and part such as equal dimethyl-ethylenediamine, by the 2-oxo piperazine coupling of formula (13) bromo or iodo acid amides and protection, so that formula (14) oxo piperazine to be provided.Preferably under inert atmosphere, under mineral alkali such as salt of wormwood exists, carry out this reaction in sealed vessel.This reaction is carried out in such as NMP at inert solvent at 80-150 ℃ of temperature.
In scheme 4, step C, under existing, benzamide makes the selective reduction of oxo piperazine, so that formula (15) piperazine to be provided.Utilize reductive agent such as borane (borane)-dimethyl sulphide complex compound to carry out 1-4 hour at inert solvent in such as THF at 0-40 ℃ of temperature, complete this reaction.Can order about and react with extra borane-dimethyl sulphide complex compound.
Selectively, in step D, in linked reaction, utilize N-tert-butoxycarbonyl piperazine to make piperazine and iodo or bromo-acid amide (13) direct reaction.This reaction is carried out under the existence such as three tertiary Ding Ji Phosphonium a tetrafluoro borates such as chlorination Allylpalladium (II) dimer and part at the Pd catalyzer.At the temperature of 20-120 ℃, inert solvent such as DMSO in, use alkali such as sodium tert-butoxide, 0.5～8 hour used time, to provide formula (15) piperazine.
In step e, remove the boc protecting group, to provide the unprotected piperazine of formula (16).For removing the acidic conditions of boc group, such as the HCl/ dioxane, be well-known in the art.
Subsequently, in step F, make unprotected amine (16) and 3-oxetanone reduction amination, so that formula (17) oxetanyl piperazine to be provided.For realizing that the whole bag of tricks of reduction amination is well-known in the art.Preferred condition is to use reductive agent such as the triacetoxyl group sodium borohydride, inert solvent such as acetonitrile in.About 0.5-4 hour is carried out in this reaction under 0-40 ℃.Can add extra triacetoxyl group sodium borohydride and 3-oxetanone to react to order about.Selectively, can be under molecular sieve exists, solvent mixture such as MeOH and Glacial acetic acid in, utilize reductive agent such as sodium cyanoborohydride to complete this reaction.This reaction is carried out about 1-24 hour at 0-60 ℃ of temperature.
In scheme 4, step G, make the alcohol (17) of oxetanyl piperazine be converted into formula I carbamate.For those skilled in the art, the existing multiple means that can be used for synthesis of carbamates, such as triphosgene/amine, chloroformic acid 4-nitro phenyl ester/amine, CDI/ amine, or isocyanate reaction direct and that suitably replace.Be used for wherein Z=-CH
2-the preferred method of the compounds of this invention use suitable isocyanic ester (O=C=N-R
2).For example, in aprotic solvent such as methylene dichloride, dioxane or preferred THF, at organic bases, such as DMAP or under preferably 4-pyrrolidino pyridine exists, with methyl isocyanate, process alcohol (17).About 2-16 hour is carried out in this reaction under 20-70 ℃ in sealed vessel.Wherein carbamate moiety is primary carbamate (R
2=H) the compounds of this invention can utilize CDI/ ammonia, Zassol or isocyanic acid chlorine sulfo group ester to synthesize.Other method is used the isocyanic acid tribromo-acetyl base ester in aprotic solvent.Subsequently, utilize neutral Al
2o
3or organic acid is such as tosic acid cracking tribromo-acetyl base.Preferred method for the synthesis of the carbamate of formula I is to use CDI, inert solvent such as THF in, under 0-25 ℃, used time 4-20 hour, form imidazoles N-manthanoate with original position.Subsequently with suitable amine (H
2nR
2) reaction formula I carbamate is provided.
One of skill in the art will appreciate that above-mentioned intermediate can be used as racemic mixture and carries out always, and in the end a step splits, preferably split by chirality HPLC, so that the compound of enantiomer-pure to be provided.
Preparation 1
6-bromine chroman-4-alcohol
At room temperature, with 3 hours bromo-3 to 7-, 4-dihydronaphthalene-1 (2H) ketone (3.95 kg, 17.4 mol) adds sodium borohydride (221 g, 5.84 mol) in the suspension of ethanol (20 L) in batches.The red solution of concentrating clarifying.Residue is added in ice (approximately 3 kg) to form suspension, then under agitation by ice-cooled 0.5M HCl(10 L) add in above-mentioned suspension.Extract this mixture with methyl tertiary butyl ether (20 L and 5 L).The organic phase merged with saturated sodium bicarbonate aqueous solution (10 L) and salt solution (2 * 10 L) washing, under reduced pressure concentrated solvent, and the solid drying that will wet in air spends the night, and obtains title compound, is light yellow solid (4.10 kg, quantitative).LC-ES/MS m/z 211 [M-H
2O+H]
+。
Basically according to the program described in preparation 1, utilize suitable ketone to prepare the alcohol in following table.
| Preparation | Chemical name | Structure | LC-ES/MS m/z（ 79Br/ 81Br） |
| 2 | Expire-1-alcohol of 7-bromonaphthalene |
 |
209/211 [M-H 2O+H] + |
| 3 | 2-is bromo-6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-9-alcohol |
 |
GC/MS 222/224 [M+] |
| 4 | 7-is bromo-2,3,4,5-tetrahydrochysene-1-benzo oxa- -5-alcohol |
 |
265/267 [M+Na] + |
Preparation 5
The bromo-2H-chromene of 6-
At room temperature, add tosic acid monohydrate (95 g, 499.42 mmol) to 6-bromine chroman-4-alcohol (3.98 kg, 17.4 mol) in the solution of toluene (18 L).Connect the Dean-Stark water trap, reflux 3 hours 50 minutes.Make mixture be cooled to 50 ℃ in air, and under agitation in impouring saturated sodium bicarbonate aqueous solution (10 L) and ice (approximately 3 kg).By two separate.With methyl tertiary butyl ether (4 L) reextraction water layer.With saturated sodium bicarbonate aqueous solution (10 L) and salt solution (1 * 10 L) washing organic layer, the vapourisation under reduced pressure solvent, obtain title compound, for brown oil (4.90 kg, > 100%, contains toluene).LCMS m/z（
79Br）209 [M+H]
+。
Basically according to the program described in preparation 5, utilize suitable alcohol to prepare the alkene in following table.
| Preparation | Chemical name | Structure | GC/MS m/z（ 79Br/ 81Br） |
| 6 | 6-is bromo-1, the 2-dihydronaphthalene |
 |
208/210 [M+] |
| 7 | 2-is bromo-6,7-dihydro-5H-benzo [7] annulene |
 |
222/224 [M+] |
| 8 | 7-is bromo-2,3-dihydro-1-benzo oxa-
 |
 |
N/A |
Preparation 9
Racemize-trans-3,6-dibromo chroman-4-alcohol
At room temperature to DMSO(16 L) and the solution of water (2.5 L) in add the bromo-2H-chromene of 6-(4.90 kg, 23.2 mol).With within 3.5 hours, add NBS(3.47 kg, 19.5 mol in batches).In mixture impouring methyl tertiary butyl ether (12 L) and water (18 L), by two separate.With saturated sodium bicarbonate (7 L), water (8 L) and salt solution (2 * 8 L) washing organic layer.With methyl tertiary butyl ether (4 L) reextraction water layer, and the solvent of the organic layer of vapourisation under reduced pressure merging, obtain title compound, be reddish-brown solid (5.10 kg, 71%).
Preparation 10
The bromo-chroman of (3R, 4S)-4-amino-6--3-alcohol
At room temperature, to racemize-trans-3,6-dibromo chroman-4-alcohol (5.10 kg, 16.6 mol) is disposable in the solution of tetrahydrofuran (THF) (5.0 L) and ethanol (5.0 L) to add ammonium hydroxide (13.0 L) and slowly was heated to 43 ℃, continuation heating 14 hours with 2 hours.Under reduced pressure concentrated this mixture is to remove approximately 9 L solvents.Methyl tertiary butyl ether (10 L) is added in remaining slurry, and stir this mixture 3 hours under 25 ℃.Collecting precipitation thing after filtration, water (2 * 2 L) washing, then use methyl tertiary butyl ether (3 * 1.5 L) washing, obtains wet solid.At room temperature at air drying, spend the night, obtain title compound, be light yellow solid (2.78 kg, 69%).LC-ES/MS m/z（
79Br）244 [M+H]
+。By with every part of 100 g on 11 * 33 cm CHIRALPAK AD 20 μ m posts with 100% methyl alcohol (the stable state recirculation is purified) wash-out containing 0.2% dimethylethyl amine, separate enantiomer, obtain 3S, 4R enantiomer (isomer 1,1362.5 g, 97.4% ee) and title compound (isomer 2,1323.7 g, 97.5% ee).Analytical chirality HPLC analysis condition: 4.6 * 150 mm CHIRALPAK AD-H 5 μ m posts, containing 100% methyl alcohol of 0.2% dimethylethyl amine, flow velocity 0.5 mL/ minute, isomer 1 T
r=4.69 minutes, isomer 2 T
r=6.27 minutes.
Preparation 11
The bromo-1a of racemize-cis-6-, 2,3,7b-tetrahydrochysene naphtho-[1,2-b] oxyethylene
Bromo-1 to 6-, 2-dihydronaphthalene (250 g, 1.20 mol) adds saturated sodium bicarbonate aqueous solution (1250 mL) and is cooled to 0-5 ℃ in the solution of methylene dichloride (3.75 L).Add MCPBA(77%, 275 g, 1.23 mol, 1.03 eq) in batches.In this mixture of 0-5 ℃ of lower mechanical stirring 1.5 hours, make it to be warmed to room temperature.At room temperature stir about is 1.5 hours, at room temperature adds extra MCPBA(77%, 15.0 g, 67 mmol, 0.05 eq) and stir about 1 hour.With methylene dichloride (3750 mL) dilution mixture, separate each layer.With saturated sodium bicarbonate aqueous solution (3 L) washing organic layer.10% aqueous solution of sodium bisulfite (3750 mL) and saturated sodium bicarbonate aqueous solution (1250 mL) are mixed, make approximately 7 solution of final pH.This solution is added in dichloromethane layer, and at room temperature stir about is 10 minutes.Separate each layer, with saturated sodium bicarbonate aqueous solution (3 L) and salt solution (3 L) washing organic layer.Concentrated in a vacuum, obtain title compound, be oil (263 g, 98%).GC/MS m/z（
79Br/
81Br）224/226 [M
+]。
Basically according to the program described in preparation 11, utilize suitable alkene to prepare the epoxide in following table.
| Preparation | Chemical name | Structure | GC/MS m/z（ 79Br/ 81Br） |
| 12 | 2-is bromo-6,7-dihydro-5H-benzo [7] wheel olefinic oxide |
 |
238/240 [M+] |
| 13 | 7-is bromo-2,3-dihydro-1-benzo oxa-
 |
 |
LC-ES/MS m/z（ 79Br/ 81Br）241/243 [M+H] + |
Preparation 14
The bromo-tetralin of racemize-anti-form-1-amino-7--2-alcohol
In the 2L pressure reactor of mechanical stirrer is housed, by the bromo-1a of racemize-cis-6-, 2,3,7b-tetrahydrochysene naphtho-[1,2-b] oxyethylene (67.0 g, 298 mmol) is dissolved in tetrahydrofuran (THF) (200 mL).Add 7M ammonia/methyl alcohol (350 mL), sealed reactor stirs 2 days under 70 ℃.Add extra 7M ammonia/methyl alcohol (140 mL), sealed reactor stirs 1 day under 70 ℃.The concentration response slurry, obtain residue (68.1 g) in a vacuum.Add ether (760 mL), at room temperature stir slurry approximately 5 hours.Collect after filtration solid, rinse with ether (2 * 215 mL), dried overnight, obtain title compound (58.1 g, 81%).GC/MS m/z（
79Br/
81Br）224/226 [M-NH
2]
+。
Basically according to the program described in preparation 14, utilize suitable epoxide to prepare the amino alcohol in following table.
| Preparation | Chemical name | Structure | LC-ES/MS m/z（ 79Br/ 81Br） |
| 15 | Racemize-trans-5-amino-3-is bromo-6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-6-alcohol |
 |
256/258 [M+H] + |
| 16 | Racemize-trans-5-amino-7-is bromo-2,3,4,5-tetrahydrochysene-1-benzo oxa-
 |
 |
258/260 [M+H] + |
Preparation 17
(1S, 2S)-1-amino-7-is bromo-1,2,3,4-naphthane-2-alcohol (2S, 3S)-2, two (the 4-toluyl oxygen base) succinates of 3-
By the disposable racemize-anti-form-1-amino-7-bromo-1 that adds of (+)-bis--Isosorbide-5-Nitrae-methyl benzoyl-D-tartrate (2.30 kg, 5.95 mol); 2; 3,4-naphthane-2-alcohol (1.40 kg, 5.78 mol) is in the solution of acetonitrile (16.0 L) and water (3.50 L).Under nitrogen, dense suspension is heated to backflow (77 ℃) and continues 30 minutes.Until approximately 46 ℃, agitator just starts to stir.Turn off the heating to oil bath, under agitation allow mixture be cooled to room temperature.After 5 hours, through Büchner funnel, filter dense slurry, rinse with acetonitrile (2 L).Continue to filter 1 hour, until no longer collect solvent.At room temperature at the air drying wet cake, spend the night, obtain desirable salt, be yellow solid (1.70 kg).Solid is added in acetonitrile (15 L) and water (3.3 L), under agitation the dense slurry of gained is heated to reflux (77 ℃) under nitrogen, continue 30 minutes.Turn off the heating to oil bath, under agitation make it be cooled to room temperature.After 5 hours, through Büchner funnel, filter dense slurry, rinse with acetonitrile (2 L).Continue filter 23 0 minute, until no longer collect solvent.At room temperature the dry wet filter cake is 48 hours, obtains desirable salt, is light yellow solid (800 g, 22%).LC-ES/MS m/z(
79br) 242 [M+H]
+(for free alkali).99.0% ee。Carry out by supercritical fluid chromatography (SFC) analysis condition that enantiomer is crossed flow measurement: post: CHIRALPAK AD-H(0.46 * 250 mm, 5 μ m), carbonic acid gas flow velocity: 2.55 mL/min., solubility promoter: containing the methyl alcohol of 0.1% diethylamide, solubility promoter flow velocity: 0.45 mL/min., back-pressure: 150 bar, column temperature: 40.9 ℃.Isomer 1 T
r=7.36 minutes, 0.5% area; Isomer 2(title compound) T
r=8.46 minutes, 99.5% area.
Preparation 18
N-[(1S, 2S)-6-amino-2-hydroxyl-indane-1-yl] t-butyl carbamate
Basically according to the document program (Kozhushkov, S.I. etc.
adv. Synth. Catal.2005,
347, 255-265), obtain>and N-[(1S, the 2S of 97% ee)-2-hydroxyl-6-nitro-indane-1-yl] t-butyl carbamate.Utilize with for 1R, the identical programe reduction nitro of 2R enantiomer described (US 7,326,731 B2), obtain title compound.
Preparation 19
N-[(1S, 2S)-the iodo-indane of 2-hydroxyl-6--1-yl] t-butyl carbamate
In ice bath, by N-[(1S, 2S)-6-amino-2-hydroxyl-indane-1-yl] t-butyl carbamate (25.0 g, 94.6 mmol) is in cooling 30 minutes of the suspension of acetonitrile (800 mL), the disposable tosic acid monohydrate (53.97 g, 283.7 mmol) that adds.With 5 minutes, Sodium Nitrite (13.05 g, 189.2 mmol) is added in mixture in the solution of water (30 mL) in batches, stir 30 minutes.In ice bath, with 10 minutes, potassiumiodide (39.25 g, 236.5 mmol) is dropwise added in mixture in the solution of water (50 mL), stir 20 minutes.Allow mixture be warmed to room temperature, and stir 1.5 hours.With 10% aqueous sodium carbonate, make dark red solution be alkalescence.Concentrate in a vacuum the gained mixture, to remove acetonitrile.Collect after filtration brown precipitate, in vacuum drying oven, 50 ℃ of lower dried overnight, obtain title compound (33.9 g, 96%).LC-ES/MS m/z 320 [M+H]
+。
Preparation 20
N-[(3R, 4S)-the bromo-3-hydroxyl-chroman of 6--4-yl]-the fluoro-benzamide of 4-
Under 17 ℃, to (3R, the bromo-chroman of 4S)-4-amino-6--3-alcohol (692 g, 2.84) and sodium bicarbonate (476 g, 5.67 mol) in the suspension of tetrahydrofuran (THF) (3.0 L) and water (3.0 L), dropwise added 4-fluorobenzoyl chloride (369 mL, 3.12 mol) with 15 minutes through feed hopper, and stir 2 hours.Add water (2 L) and methyl tertiary butyl ether (3.5 L), stir 5 minutes.Separate organic phase, water (2 L) and salt solution (2 L) washing.Use the anhydrous magnesium sulfate drying organic moiety, concentrated in a vacuum, obtain light yellow solid (2.3 kg).Under 25 ℃, abrasive solid 3 h in heptane (5 L).Collect after filtration, in baking oven under 50 ℃ dry 12 hours, obtain title compound (975 g, 94%), be white solid.LC-ES/MS m/z（
79Br/
81Br）366/368 [M+H]
+。
Basically according to the program described in preparation 20, utilize the amino alcohol free alkali of suitable racemize or enantiomer-pure or salt to prepare the acid amides in following table.When using the salt (preparation 21) of amino alcohol, use saturated sodium bicarbonate as alkali.
| Preparation | Chemical name | Structure | LC-ES/MS m/z（ 79Br/ 81Br） |
| 21 | N-[(1S, 2S)-the bromo-2-hydroxyl-tetralin of 7--1-yl]-the fluoro-benzamide of 4- |
 |
362/364 [M+H] + |
| 22 | The bromo-8-hydroxyl-6,7,8 of racemize-trans-N-[2-, 9-tetrahydrochysene-5H-benzo [7] annulene-9-yl]-the fluoro-benzamide of 4- |
 |
376/378 [M+H] + |
| 23 | The bromo-4-hydroxyl-2,3,4 of racemize-trans-N-[7-, 5-tetrahydrochysene-1-benzo oxa- -5-yl]-the fluoro-benzamide of 4- | 380/382 [M+H] + |
Preparation 24
4-fluoro-N-[(1S, 2S)-the iodo-indane of 2-hydroxyl-6--1-yl] benzamide
At room temperature, to N-[(1S, 2S)-the iodo-indane of 2-hydroxyl-6--1-yl] t-butyl carbamate (39.6 mmol, 14.9 g) is in 1, in the solution of 4-dioxane (200 mL), add 4M hydrogenchloride in the solution of dioxane (100 mL), stir 2 hours.Concentrated gained suspension in a vacuum, and in vacuum drying oven dry 48 hours.Resistates is dissolved in to THF(25 mL), in ice bath cooling 30 minutes.Dropwise add 5 M aqueous sodium hydroxide solutions (17.4 mL, 87.2 mmol) and 4-fluorobenzoyl chloride (3.78 mL, 40.4 mmol).Make solution be warmed to room temperature, and stir 1 hour.Concentrate in a vacuum dark solution, water (50 mL) dilution.Collect after filtration solid, in vacuum drying oven, 40 ℃ of lower dried overnight, obtain title compound (14.4 g, 91%).LC-ES/MS m/z 398 [M+H]
+。
Preparation 25
4-[(2S, 3S)-the 3-[(4-fluoro benzoyl) amino]-2-hydroxyl-indane-5-yl]-3-oxo-piperazine-1-t-butyl formate
With the fluoro-N-[(1S of nitrogen purging 4-, the iodo-indane of 2S)-2-hydroxyl-6--1-yl] benzamide (8.70 g, 21.9 mmol), 4-N-boc-2-oxo-piperazine (4.61 g, 22.3 mmol) and salt of wormwood (6.12 g, 43.8) in the mixture of N-Methyl pyrrolidone (100 mL).Add cupric iodide (I) (2.11 g, 11.0 mmol) and equal dimethyl-ethylenediamine (2.34 mL, 21.9 mmol).Use the diaphragm seal flask, stir 6 hours under 100 ℃.Mixture is cooled to room temperature, with ethyl acetate (100 mL) dilution.Water (3 * 100 mL) washing organic moiety, then use the salt water washing, afterwards through dried over sodium sulfate, filters, and be concentrated into dry.Through column chromatography (120 g silicon-dioxide, 2-5% methyl alcohol/chloroform) purifying resistates, obtain title compound (7.63 g, 74%).LC-ES/MS m/z 470 [M+H]
+。
Preparation 26
4-[(3S, 4S)-the 4-[(4-fluoro benzoyl) amino]-3-hydroxyl-tetralin-6-yl]-3-oxo-piperazine-1-t-butyl formate
Basically according to for 4-[(2S; 3S)-3-[(4-fluoro benzoyl) amino]-2-hydroxyl-indane-5-yl]-preparation 25 of 3-oxo-piperazine-1-t-butyl formate; use N-[(1S, 2S)-the bromo-2-hydroxyl-tetralin of 7--1-yl]-the fluoro-benzamide of 4-prepares title compound.LC-ES/MS m/z 484 [M+H]
+。
Preparation 27
4-[(2S, 3S)-the 3-[(4-fluoro benzoyl) amino]-2-hydroxyl-indane-5-yl] piperazine-1-t-butyl formate
In ice bath by 4-[(2S; 3S)-3-[(4-fluoro benzoyl) amino]-2-hydroxyl-indane-5-yl]-3-oxo-piperazine-1-t-butyl formate (8.85 g; 18.9 mmol) in cooling 30 minutes of the solution of anhydrous tetrahydro furan (40 mL); and add borane-dimethyl sulphide complex compound (2M under nitrogen; 37.7 mL, 75.40 mmol).Make mixture be warmed to room temperature, and stir 1.5 hours.At room temperature add second part of borane-dimethyl sulphide complex compound (2M, 9.42 mL, 18.9 mmol), and stir 1 hour.In ice bath cooling 10 minutes, dropwise add carefully water, then add saturated sodium bicarbonate solution (50 mL).With ethyl acetate (150 mL) dilution gained suspension.By salt water washing organic moiety, through dried over sodium sulfate, and concentrated in a vacuum.Through flash chromatography (120 g silicon-dioxide, 40-50% ethyl acetate/hexane) purification of crude product, obtain title compound (6.8 g, 79%).LC-ES/MS m/z 456 [M+H]
+。
Preparation 28
4-[(3S, 4S)-the 4-[(4-fluoro benzoyl) amino]-3-hydroxyl-tetralin-6-yl] piperazine-1-t-butyl formate
Basically according to for 4-[(2S; 3S)-3-[(4-fluoro benzoyl) amino]-2-hydroxyl-indane-5-yl] preparation 27 of piperazine-1-t-butyl formate; use 4-[(3S, 4S)-the 4-[(4-fluoro benzoyl) amino]-3-hydroxyl-tetralin-6-yl]-3-oxo-piperazine-1-t-butyl formate prepares title compound.LC-ES/MS m/z 470 [M+H]
+。
Preparation 29
4-fluoro-N-[(1S, 2S)-2-hydroxyl-7-piperazine-1-base-tetralin-1-yl] benzamide hydrochloride salt
At room temperature; to 4-[(3S; 4S)-4-[(4-fluoro benzoyl) amino]-3-hydroxyl-tetralin-6-yl] piperazine-1-t-butyl formate (19.4 g, 41.3 mmol) adds 4M hydrogenchloride/dioxane (135 mL) in the solution of Isosorbide-5-Nitrae-dioxane (430 mL).50 ℃ of lower mechanical stirring gained slurry 13 hours.Concentrated this reaction in a vacuum, obtain title compound (24.8 g, quantitative).LC-ES/MS m/z 370 [M+H]
+。
Preparation 30
4-fluoro-N-[(3R, 4S)-3-hydroxyl-6-piperazine-1-base-chroman-4-yl] benzamide hydrochloride salt
At room temperature, under agitation make three tertiary Ding Ji Phosphonium a tetrafluoro borates (16.0 g, 54.6 mmol) and chlorination Allylpalladium (II) dimer (5.07 g, 27.3 mmol) in DMSO(1.40 L) suspension degassed (nitrogen bubble is passed to mixture).Add N-tert-butoxycarbonyl piperazine (97% is pure for 315 g, 1.64 mol) and N-[(3R, 4S)-the bromo-3-hydroxyl-chroman of 6--4-yl]-the fluoro-benzamide of 4-(200.0 g, 546 mmol).Mixture is stirred 15 minutes to then heating under 80 ℃ under nitrogen.Add sodium tert-butoxide (179 g, 1.80 mol), under 93-98 ℃, heating is 45 minutes.Solution by mixture impouring 1M phosphoric acid (2.73 L, 2.73 mol are adjusted to pH=2.3 with 50% sodium hydroxide) and ethyl acetate (800 mL), stir 10 minutes.Separate each layer, and by ethyl acetate (3 * 300 mL) aqueous layer extracted.The organic layer merged with half saturated brine (2 * 500 mL) washing.Process organic layer with activated carbon (20 g) and silica gel (200 g), stir 30 minutes.Through Celite pad, filter, under reduced pressure concentrated, obtain dark oil.Oil is dissolved in to methyl alcohol (800 mL), adds 4M hydrogenchloride/dioxane (410 mL), and 40 ℃ of lower stirred solutions 1 hour.Evaporating solvent, be suspended in resistates in acetonitrile (1.6 L) and at room temperature stir 1 hour in a vacuum.Collect after filtration solid to avoid the hydration of salt under nitrogen.With acetonitrile (500 mL) and methyl tertiary butyl ether (1 L) wash filtrate, dry under vacuum, obtain title compound (262 g, 73%).LC-ES/MS m/z 372 [M+H]
+。
Basically according to the program described in preparation 30, utilize the bromide of suitable racemize or enantiomer-pure to prepare the amine in following table.
| Preparation | Chemical name | Structure | LC-ES/MS m/z |
| 31 | The fluoro-N-[6-hydroxyl of racemize-trans-4--3-piperazine-1-base-6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-5-yl] benzamide hydrochloride salt |
 |
384 [M+H] + |
| 32 | The fluoro-N-[4-hydroxyl of racemize-trans-4--7-piperazine-1-base-2,3,4,5-tetrahydrochysene-1-benzo oxa-
 |
386 [M+H] + |
Preparation 33
4-fluoro-N-[(3R, 4S)-3-hydroxyl-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-4-yl] benzamide
By triacetoxyl group sodium borohydride (20 g, 94.4 mmol) add the fluoro-N-[(3R of 4-, 4S)-3-hydroxyl-6-piperazine-1-base-chroman-4-yl] benzamide hydrochloride salt (32.0 g, 78.5 mmol) and 3-oxetanone (6.87 g, 98.1 mmol) in the slurry of acetonitrile (300 mL).Slurry is stirred 20 minutes to the disposable more triacetoxyl group sodium borohydride (20 g, 94.4 mmol) that adds.Under 28 ℃ by brown mixture stir about 2 hours.Add extra triacetoxyl group sodium borohydride (10 g, 47.2 mmol), mixture is stirred 30 minutes.Add 3-oxetanone (2 g, 28.6 mmol), added extra 3-oxetanone (1 g, 14.3 mmol) after 20 minutes.Stir 30 minutes, by mixture impouring saturated sodium bicarbonate aqueous solution solution (1 L), and add methylene dichloride (1 L).Separate organic layer, concentrated in a vacuum, obtain light gray solid.Through the purification by silica gel column chromatography solid, with 3-6% Virahol/methylene dichloride wash-out, obtain title compound, be white solid (19.2 g, 73%).LC-ES/MS m/z 428 [M+H]
+。
Basically according to the program described in preparation 33, utilize the amine of suitable racemize or enantiomer-pure to prepare the trimethylene oxide in following table.
| Preparation | Chemical name | Structure | LC-ES/MS m/z |
| 34 | 4-fluoro-N-[(1S, 2S)-2-hydroxyl-7-[4-(trimethylene oxide-3-yl) piperazine-1-yl] tetralin-1-yl] benzamide |
 |
426 [M+H] + |
| 35 | The fluoro-N-[8-hydroxyl-2-[4-of racemize-trans-4-(trimethylene oxide-3-yl) piperazine-1-yl]-6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-9-yl] benzamide | 440 [M+H] + | |
| 36 | The fluoro-N-[4-hydroxyl-7-[4-of racemize-trans-4-(trimethylene oxide-3-yl) piperazine-1-yl]-2,3,4,5-tetrahydrochysene-1-benzo oxa-
 |
442 [M+H] + |
Preparation 37
4-fluoro-N-[(1S, 2S)-2-hydroxyl-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] indane-1-yl] benzamide
At room temperature; to 4-[(2S; 3S)-3-[(4-fluoro benzoyl) amino]-2-hydroxyl-indane-5-yl] piperazine-1-t-butyl formate (300 mg; 0.659 mmol) in 1; add 4M hydrogenchloride/dioxane (5.0 mL) in the solution of 4-dioxane (5.0 mL), and stir 1 hour.Concentrated suspension liquid in a vacuum.Add saturated sodium bicarbonate aqueous solution (50 mL) in resistates, and extract by ethyl acetate (3 * 50 mL).The organic layer merged with the salt water washing, through dried over sodium sulfate, and concentrated in a vacuum.Resistates is dissolved in methyl alcohol (20 mL), adds activity 4 molecular sieves of 3-oxetanone (142 mg, 1.98 mmol), Glacial acetic acid (170 μ L, 2.96 mmol) and crushing.Under 50 ℃ by gained suspension agitation 1 hour.At room temperature add sodium cyanoborohydride (131 mg, 1.98 mmol), stirring is spent the night.Add saturated sodium bicarbonate solution (20 mL), stir 20 minutes.With methylene dichloride (3 * 50 mL) extraction, the organic layer that water and salt water washing merge.Through the dried over sodium sulfate organic moiety, filter, and concentrated, obtain title compound (220 mg, 81%).LC-ES/MS m/z 412 [M+H]
+。
Preparation 38
Racemize-trans-3,6-dibromo chroman-4-alcohol
6-bromine chroman-4-alcohol (25.0 g, 109.1 mmol) is heated to 100 ℃ in the solution of toluene (500 mL).Add tosic acid monohydrate (1.1 g, 5.5 mmol), through utilizing the Dean-Stark water trap, collect water, stir 2 hours under 100 ℃.Remove thermal source, with ice-cold 0.5N NaOH(250 mL) the quencher reaction mixture.Further reaction mixture is cooled to 5-10 ℃, then separates each layer.Water (25 mL) washing organic layer, and under reduced pressure concentrated organism to the pact of its original volume half.Add DMSO(100 mL), continue under reduced pressure concentrated until no longer distill out toluene.
The DMSO solution of intermediate alkene is cooled to 0-5 ℃, adds water (17 mL) and be cooled to again 0-5 ℃.Divide five parts with 30 minutes and add N-bromosuccinimide (21.7 g, 120.0 mmol).Under 0-5 ℃, stir 1 hour.With ethyl acetate (100 mL) and water (50 mL) diluted reaction mixture, stir 10 minutes, separate each layer.With ethyl acetate (100 mL) reextraction water layer.The organism merged with 1:1 brine (2 * 50 mL) washing, through dried over sodium sulfate, and under reduced pressure concentrated, obtain title compound, be white solid (33.0 g, 99%).
1H NMR（DMSO-
d 6）δ 4.26（m，1H），4.37（m，2H），4.65（m，1H），6.27（d，1H），6.80（d，1H），7.35（dd，1H），7.46（bd，1H）。GC/MS m/z（
79Br/
81Br）308/310 [M
+]。
Preparation 39
The bromo-chroman of racemize-trans-4-amino-6--3-alcohol
At ambient temperature, to racemize-trans-3,6-dibromo chroman-4-alcohol (30.0 g, 97.4 mmol) in the solution of Virahol (300 mL) (500 mL), add ammonium hydroxide (the 28-30% aqueous solution, 150 mL, 2.2 mol).Slowly stir 15 hours.Filter reaction mixture, water (200 mL) dilution filtrate.Under reduced pressure concentrated gained solution is to half of its initial weight.Add water (100 mL), at ambient temperature mixture is stirred 10 minutes, then be cooled to 0-5 ℃ and also stir again 30 minutes.Collecting precipitation after filtration, water (25 mL) and heptane (25 mL) washing solid.At 40 ℃ of lower vacuum-drying materials, obtain title compound, be light yellow solid (21.2 g, 89.2%).
1H NMR（DMSO-
d 6）δ 1.96（bs，2H），3.53（m，2H），3.87（dd，1H），4.11（dd，1H），5.15（bs，1H），6.66（d，1H），7.19（dd，1H），7.48（dd，1H）。LC-ES/MS m/z（
79Br）244 [M+H]。
Preparation 40
The bromo-chroman of (3R, 4S)-4-amino-6--3-alcohol
By racemize-trans-4-amino-6-bromine chroman-3-alcohol (21.1 g, 86.4 mmol), D-(+)-dextrocamphoric acid (17.3 g, 86.4 mmol), the mixture of acetonitrile (633 mL) and water (47.6 mL) is heated to 70-75 ℃, and stirs 10 minutes.With 4 hours, allow solution be cooled to envrionment temperature.At ambient temperature after 24 hours, filtering mixt.Use 7% H
2o/ acetonitrile (2 * 20 mL) rinses solid.Filtrate is heated to 50 ℃, adds 1N NaOH(216.1 mL).Under reduced pressure concentrate the gained mixture, to remove acetonitrile.Add H
2o(211 mL), solution is heated to 70 ℃.Be cooled to envrionment temperature, after filtration collecting precipitation.Water (25 mL) washing, spend the night 50 ℃ of lower vacuum-dryings, obtains title compound, is white solid (9.8 g, 46.4%, 98.7% ee in 50% theoretical weight).
Rough (3R, 4S)-4-amino-6-bromine chroman-3-alcohol (1.5 g, 6.15 mmol), acetonitrile (12.0 mL) and water (3.0 mL) are merged, be heated to 70-75 ℃.By solution stirring 30 minutes, allow solution be cooled to envrionment temperature, and then stir 1 hour.Mixture is cooled to 0-5 ℃, and stirs 30 minutes.Cross filter solid, with cold 4:1 acetonitrile: H
2o(10 mL) washing.Spend the night at 50 ℃ of lower vacuum-drying solids, obtain the title compound of purifying, be white solid (1.1 g, 74.6%, 99.7% ee).
1H NMR（DMSO-
d 6）δ 1.96（bs，2H），3.53（m，2H），3.87（dd，1H），4.11（dd，1H），5.15（bs，1H），6.66（d，1H），7.19（dd，1H），7.48（dd，1H）。LC-ES/MS m/z（
79Br）244 [M+H]。Analytical chirality HPLC analysis condition: ChiralPak AD-H post (150 * 4.6mm, 4.6 microns); Flow velocity 0.6 mL/min; Wavelength 290 nm; Elutriant 100% methyl alcohol+0.2% v/v dimethylethyl amine; 10 minutes working times; 30 ℃ of column temperatures; Isocratic elution.
Preparation 41
4-fluoro-N-[(3R, 4S)-3-hydroxyl-6-(piperazine-1-yl) chroman-4-yl] benzamide
At ambient temperature, to the bromo-chroman of (3R, 4S)-4-amino-6--3-alcohol (10.0 g, 41.0 mmol) in THF(50 mL) suspension in, add sodium bicarbonate (5.2 g, 61.4 mmol) and water (50 mL).Stir 5 minutes, mixture is cooled to 0-5 ℃.Dropwise added the fluoro-Benzoyl chloride of 4-(6.5 g, 41.0 mmol) with 10 minutes through feed hopper.Mixture is stirred 30 minutes under 0-5 ℃, make mixture be warmed to 15-20 ℃, then stir 2 hours.With salt solution (50 mL) and THF(50 mL) the dilution mixture, and stir 20 minutes.Separate each layer, concentrated organic layer is to half of its original volume.To add THF(50 mL) and be concentrated into half volume triplicate or until the Karl Fisher water analysis of solution<0.1%.Add DMSO(100 mL), continue under 50 ℃ under reduced pressure enriched mixture until no longer distill out THF.
Use DMSO(200 mL) and the DMSO solution of toluene (45 mL) dilution gained amide intermediate, and utilize under the nitrogen surface and spray (sub-surface sparge) and come degassed 30 minutes.Add piperazine (16.6 g, 192.7 mmol), to solution degassed 30 minutes.Solution is heated to 40 ℃, adds chlorination Allylpalladium (II) dimer (0.72 g, 2 mmol) and three tertiary Ding Ji Phosphonium a tetrafluoro borates (1.19 g, 4 mmol) under blanket of nitrogen.Mixture is stirred 10 minutes, add sodium tert-butoxide (13.0 g, 135.3 mmol) under blanket of nitrogen.Improve internal temperature to 70 ℃, mixture is stirred 4 hours.Reactor content is cooled to 20 ℃, added water (75 mL) through 15 minutes.Utilize 6N HCl by the pH regulator of mixture to 6-7, add ethyl acetate (150 mL).Reactor content is stirred 30 minutes, then separate each layer.With ethyl acetate (2 * 150 mL) reextraction water layer.Discard acetic acid ethyl acetate extract, utilize the NaOH(40% aqueous solution) by the pH regulator of water layer to 11-12.By ethyl acetate (3 * 150 mL) aqueous layer extracted.Merge organic extract liquid, under reduced pressure be concentrated into its original volume pact half.Add activated carbon (1.5g), mixture is heated to 50-55 ℃.Stir 1 hour under 50-55 ℃, mixture is cooled to 20 ℃, solids removed by filtration.With salt solution (2 * 300 mL) wash filtrate, under reduced pressure concentrate extremely approximately 2 volumes (starting raw material based on initial) of organism.Mixture is cooled to 0-5 ℃, and stirs again 3 hours.Be separated by filtration solid, with methyl tertiary butyl ether (30 mL) washing, at 50 ℃ of lower vacuum-drying solids.Reclaim title compound, be pale solid (7.9 g, 52%).
1H NMR（DMSO-
d 6）δ 2.40-2.80（bm，8H），3.65-3.95（bm，2H），4.13（d，1H），4.95（m，1H），5.35（bs，1H），6.63（dd，1H），6.69（d，1H），6.80（d，1H），7.27（m，2H），7.96（m，2H），8.72（bd，1H）。LC-ES/MS m/z 372 [M+H]。
Preparation 42
4-fluoro-N-[(3R, 4S)-3-hydroxyl-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-4-yl] benzamide
By 4-fluoro-N-[(3R, 4S)-3-hydroxyl-6-(piperazine-1-yl) chroman-4-yl] benzamide (8.2 g, 22.0 mmol) and 3-oxetanone (2.4 g, 33.0 mmol) be incorporated into THF(164 mL) in.Add acetic acid (1.3 mL, 22.0 mmol), the gained mixture is heated to 35-40 ℃.After 1 hour, add triacetoxyl group sodium borohydride (8.4 g, 39.6 mmol), stir 4 hours under 35-40 ℃.Reaction mixture is cooled to 15 ℃, with within 30 minutes, adding 2N NaOH(81.6 mL).Add salt solution (81.6 mL), mixture is stirred 30 minutes.Separate each layer, with 2N NaOH(81.6 mL) and salt solution (81.6 mL) dilution organic layer.The gained mixture is stirred 30 minutes.Separate each layer, and remove water layer.Add activated carbon (1.0 g) in organic layer, temperature is increased to 50-55 ℃, stir 1 hour.Filtering mixt is to remove solid, and under reduced pressure concentrated filtrate is to 1/10th of about original volume.Add ethyl acetate (164 mL), under reduced pressure be concentrated into 1/4th of about original volume.Repeat twice of this process by ethyl acetate (2 * 164 mL).Concentrated organism is 3 volumes (based on starting raw material) extremely approximately, improve internal temperature to 70-75 ℃, stir 2 hours.Mixture is cooled to 10 ℃, adds heptane (82 mL) with 15 minutes, then stir 2 hours.Be separated by filtration technical grade title intermediate, at 50-55 ℃ of lower vacuum-drying solid (reclaiming 10.1 g).
Purifying: by technical grade 4-fluoro-N-[(3R, 4S)-3-hydroxyl-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-4-yl] benzamide (10.0 g, 23.4 mmol) is suspended in acetonitrile (700 mL), and heated mixt is to refluxing.Stir 2 hours under refluxing, be cooled to 50-55 ℃, and add activated carbon (1.0 g).Stir 2 hours under 50-55 ℃, filter to remove solid.Under reduced pressure concentrated filtrate is to about 5 volumes (based on initial industrial raw material).Improve internal temperature to 75-80 ℃, and stir 1 hour.Mixture is cooled to 20 ℃, and stirs again 4 hours.Be separated by filtration title compound, obtain white solid (6.8 g, 72%).
1H NMR（DMSO-
d 6）δ 2.33（m，4H），2.94（m，4H），3.40（m，1H），3.85（m，1H），3.93（d，1H），4.14（d，1H），4.40（dd，2H），4.49（dd，2H），4.94（m，1H），5.34（d，1H），6.65（d，1H），6.70（d，1H），6.84（dd，1H），7.27（m，2H），7.97（m，2H），8.75（bd，1H）。LC-ES/MS m/z 428 [M+H]。
Embodiment 1
The N-methyl carbamic acid [(3R, 4S)-4-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-3-yl] ester
To the fluoro-N-[(3R of 4-, 4S)-3-hydroxyl-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-4-yl] benzamide (72.0 g, 168 mmol) in THF(648 mL) solution in add 1,1'-carbonyl dimidazoles (35.5 g, 219 mmol), at room temperature solution stirring is spent the night.Mixture is cooled to 5 ℃, dropwise adds the 2M methylamine in the solution (210 mL, 421 mmol, 2.5 eq) of THF with the times of 15 minutes.Stir 30 minutes, in the mixture of impouring water (720 mL) and methyl tertiary butyl ether (216 mL).Mixture is stirred 30 minutes to each phase of decantation.By methylene dichloride (3 * 216 mL) aqueous phase extracted.The organic phase merged with salt solution (3 * 100 mL) washing, through anhydrous sodium sulfate drying, and concentrated in a vacuum.Resistates is suspended in ethyl acetate (720 mL), and under refluxing, heating is 2 hours, is cooled to 10 ℃.Collect after filtration solid, dried overnight under vacuum, obtain title compound (64.0 g, 78%), is white solid.LC-ES/MS m/z 485 [M+H]
+。
Basically according to the program described in embodiment 1, utilize the alcohol of suitable enantiomer-pure to prepare the carbamate in following table.
| Embodiment | Chemical name | Structure | LC-ES/MS m/z |
| 2 | The N-methyl carbamic acid [(1S, 2S)-1-[(4-fluoro benzoyl) amino]-7-[4-(trimethylene oxide-3-yl) piperazine-1-yl] tetralin-2-yl] ester |
 |
483 [M+H] + |
Embodiment 3
The N-methyl carbamic acid [(8S, 9S)-9-[(4-fluoro benzoyl) amino]-2-[4-(trimethylene oxide-3-yl) piperazine-1-yl]-6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-8-yl] ester
Basically according to the program of above-described embodiment 1, utilize the fluoro-N-[8-hydroxyl-2-[4-of racemize-trans-4-(trimethylene oxide-3-yl) piperazine-1-yl]-6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-9-yl] benzamide, prepare the racemic amino manthanoate.LC-ES/MS m/z 497 [M+H]
+。By N-methyl carbamic acid racemize-trans-9-[(4-fluoro benzoyl) amino]-2-[4-(trimethylene oxide-3-yl) piperazine-1-yl]-6; 7; 8,9-tetrahydrochysene-5H-benzo [7] annulene-8-yl] ester (1.03 g) is dissolved in methylene dichloride (8 mL) and methyl alcohol (3 mL).In the upper enantiomer of by SFC, separating every part of 300 μ L of CHIRALPAK AD-H post (2.1 * 25 cm, 5 μ m).Moving phase: containing 30% Virahol of 0.2% Isopropylamine/carbonic acid gas.Flow velocity: 70 mL/min.Detect: 225 nm.Obtaining title compound, is isomer 1(333 mg, 99% ee); And 8R, the 9R enantiomer, be isomer 2(359 mg, 97.5% ee).Utilizing 30% Virahol containing 0.2% Isopropylamine/carbonic acid gas, at CHIRALPAK AD-H(4.6 * 150 mm, 5 μ m) to measure enantiomer by SFC on post excessive.Flow velocity: 5 mL/min.Detect: 225 nm.Isomer 1(title compound) T
r=1.76 minutes.Isomer 2 T
r=2.30 minutes.
Embodiment 4
The N-methyl carbamic acid [(4S, 5S)-5-[(4-fluoro benzoyl) amino]-7-[4-(trimethylene oxide-3-yl) piperazine-1-yl]-2,3,4,5-tetrahydrochysene-1-benzo oxa-
-4-yl] ester
According to the program of above-described embodiment 1, utilize the fluoro-N-[4-hydroxyl-7-[4-of racemize-trans-4-(trimethylene oxide-3-yl) piperazine-1-yl by basically]-2,3,4,5-tetrahydrochysene-1-benzo oxa-
-5-yl] benzamide, prepare the racemic amino manthanoate.LC-ES/MS m/z 499 [M+H]
+。By N-methyl carbamic acid racemize-trans-[5-[(4-fluoro benzoyl) amino]-7-[4-(trimethylene oxide-3-yl) piperazine-1-yl]-2,3,4,5-tetrahydrochysene-1-benzo oxa-
-4-yl] ester (100mg) is dissolved in methyl alcohol (3 mL), filters insoluble solid.Upper by the enantiomer of every part of chromatographic separation 1.5 mL (injecting for 2 times) at CHIRALPAK AD-H post (3 * 25 cm, 5 μ m).Moving phase: 95% ethanol/5% acetonitrile.Flow velocity: 18 mL/min.Detect: 225 nm.Obtaining title compound, is isomer 1(42 mg, 99% ee); And 4R, the 5R enantiomer, be isomer 2(40 mg, 99% ee).Utilizing 95% ethanol containing 0.2% dimethylethyl amine/5% acetonitrile, at CHIRALPAK AD-H(4.6 * 150 mm, 5 μ m) to measure enantiomer by HPLC on post excessive.Flow velocity: 1.0 mL/min.Detect: 225 nm.Isomer 1(title compound) T
r=3.58 minutes.Isomer 2 T
r=5.13 minutes.
Embodiment 5
The N-methyl carbamic acid [(1S, 2S)-1-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] indane-2-yl] ester
To the fluoro-N-[(1S of 4-, 2S)-2-hydroxyl-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] indane-1-yl] benzamide (220 mg, 0.535 mmol) add 4-pyrrolidino pyridine (16 mg in the solution of tetrahydrofuran (THF) (3.0 mL), 0.107 mmol), and be sealed in the pressure phial.Add methyl isocyanate (97 μ L, 1.60 mmol) by syringe in mixture, under 60 ℃, stir and spend the night.In ice bath, cooling gained suspension, collect white solid after filtration, and in 40 ℃ of vacuum drying ovens, drying is 3 hours, obtains title compound (200 mg, 80%).LC-ES/MS m/z 469 [M+H]
+。
Embodiment 6
The N-methyl carbamic acid [(3R, 4S)-4-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-3-yl] ester
By the fluoro-N-[(3R of 4-, 4S)-3-hydroxyl-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-4 base] benzamide (10.0 g, 23.4 mmol) is suspended in THF(200 mL) in, add 1,1 carbonyl dimidazoles (4.9 g, 30.4 mmol).Stir at ambient temperature 3 hours.Reaction mixture is cooled to-5 ℃, added 2M methylamine (in THF, 21 mL, 42.1 mmol) through 15 minutes.Under-5-0 ℃, the gained mixture is stirred 3 hours.Add 2N NaOH(100 mL), under 10-30 ℃, mixture is stirred 1 hour.Separate each layer, with 2N NaOH(4 * 100 mL) the washing organism.Add water (200 mL), under reduced pressure enriched mixture is to about 20 volumes (based on starting raw material).Add THF(200 mL), stir at ambient temperature 1 hour.Filtering mixt, be transferred back to the product wet cake in clean reaction vessel.Add THF(200 mL) and water (200 mL), stir at ambient temperature 1 hour.Be separated by filtration the technical grade title compound, at 80 ℃ of lower vacuum-dryings (9.0g, 80%).
Embodiment 7
N-methyl carbamic acid [(3R, 4S)-4-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-3-yl] crystallization/solid form of ester transforms
Under nitrogen atmosphere; by technical grade N-methyl carbamic acid [(3R; 4S)-4-[(4-fluoro benzoyl) amino]-6-[4-(trimethylene oxide-3-yl) piperazine-1-yl] chroman-3-yl] ester (50 g, 103.2 mmol) is suspended in THF(1500 mL) in.Mixture is heated to 50-60 ℃, and stirs 1 hour.Add activated carbon (5.0 g), continue to stir 1 hour under 50-60 ℃.Mixture is cooled to 40-50 ℃, and filters to remove solid.Under reduced pressure concentrated filtrate is to about 5 volumes (based on starting raw material).Add acetonitrile (1000 mL), under reduced pressure be concentrated into approximately 5 volumes.Repeat 4 times to removing whole THF, then enriched mixture is to the 10-15 volume.Mixture is heated to 70-75 ℃, and stirs 18 hours.Mixture is cooled to 15 ℃, and stirs 4 hours.Be separated by filtration white crystal, 55-60 ℃ of lower vacuum-drying, obtain title compound (42 g, 84%).
1H NMR（DMSO-
d 6）δ 2.32（m，4H），2.53（d，3H），2.96（m，4H），3.39（m，1H），4.11-4.25（m，2H），4.39（dd，2H），4.51（dd，2H），4.86（m，1H），5.04（m，1H），6.70-6.75（m，2H），6.85（dd，1H），7.17（m，1H）7.28（m，2H），7.96（m，2H），8.90（bd，1H）。LC-ES/MS m/z 485 [M+H]。Chiral analysis: 99.9%
ee.
Test example compound of the present invention in following in vitro and in vivo test.
external
The approval test of human cathepsin S and mouse tissue proteolytic enzyme S and the Choice tests of human cathepsin L, B, K, V and F are described below.Experiment condition and/or the material of each test are slightly had any different, accordingly, perhaps such difference directly is recorded in the ordinary test condition, or immediately after the ordinary test condition, in table 1, utilization identifies 1a to 1g, such difference is encoded in the corresponding enzyme test of basis.
Prepare test compounds in DMSO, to form the 10mM stock solution.Before carrying out external enzymatic test, in 96 hole circle base plates, by stock solution in DMSO serial dilution to obtain having 10 dilution curves of final compound concentration scope 1a.At test damping fluid (for whole test) hereinafter described immediately, compound is further diluted to 1b:
human cathepsin S, L, B, F and mouse tissue proteolytic enzyme S:the 50 mM sodium phosphates (pH 6.5) that contain 2.5 mM DTT and the additional 0.01% TRITON X-100 of 2.5 mM EDTA
human cathepsin K and V:the 100 mM sodium acetates (pH 5.5) that contain 100 mM NaCl, 2.5 mM DTT and the additional 0.01% TRITON X-100 of 2.5 mM EDTA.
In each hole that adds the A to H of corresponding low protein binding Xing Ban district's black dull and stereotyped (Costar 3694) to arrange each diluent of 10 μ L.The 1c amount that will prepare in damping fluid in test substrate---during benzyloxycarbonyl-L-leucyl-L-arginine-4-methyl-coumaric acyl (coumaryl)-7-acid amides (Peptide Institute) adds each hole of this flat board, final concn is 1d.The corresponding enzyme of the 1e amount that will prepare in damping fluid in test (immediately hereinafter described) causes obtaining final concn 1f, with initiation reaction in adding each hole of flat board of containing substrate and test compounds.
human cathepsin S, L, K and V:available from Calbiochem.
mouse tissue proteolytic enzyme S:in brief, utilize and contain histidine-tagged mCathepsin S-pAN51(T760) construct, clone's mouse tissue proteolytic enzyme S in baculovirus.Then purify activated protein with IMAC.
human cathepsin F:in brief, following inner preparation people recombinant tissue Protease F.Utilization contains histidine-tagged CathepsinF-pAN60(T-2188) construct, cloned tissue proteinogen F(procathepsin F in the 293E cell).Then purify this albumen with IMAC.Utilize the former F of gastric pepsin digestion tissue protein, and utilize the repurity of Mono S column chromatography, Protease F is organized in the activation that produces purifying.
On dull and stereotyped mixing tank, by the jolting in short-term of mixture low speed.At room temperature after incubation time 1g, utilize Envision 2103 Multilabel readers, under excitation wavelength 355 nm and emission wavelength 460 nm, record the RFU of mixture, 0.1 second used time.RFU is mapped to inhibitor concentration, utilizes Activity Base(ver. 7.3.2.1), to fitting of a curve, obtain IC with four parameter logistic equations
50value.For human cathepsin F, Packard Fusion Alpha microplate (0.5 second read/hole) is for measuring RFU, and GraphPad Prism 4.03 softwares are for mapping RFU to inhibitor concentration.
The experiment condition of table 1. in vitro tests
According to scheme as above basically, IC in the human cathepsin S that the embodiment compound demonstrates and the test of mouse tissue proteolytic enzyme S enzyme inhibitors
50respectively lower than 800 nM and 400 nM.Specifically, IC in the human cathepsin S enzyme inhibitors test that embodiment 1 and 2 compound demonstrate
50be respectively approximately 6.4 nM and 10.2 nM, IC in the test of mouse tissue proteolytic enzyme S enzyme inhibitors
50be respectively approximately 1.7 nM and 3.9 nM, prove that thus some compound in the scope of the invention is effective inhibitor of people and mouse tissue proteolytic enzyme S.
For human cathepsin L, B, K and the test of V enzyme inhibitors, the IC that embodiment 1 compound demonstrates
50be respectively approximately>167 μ M, 5.2 μ M, 100 μ M and 33 μ M, embodiment 2 is respectively approximately>167 μ M, 94 μ M, 100 μ M and 100 μ M.For human cathepsin F, embodiment 1 compound does not demonstrate the inhibition that reaches 30 μ M.These results prove, some compound in the scope of the invention is the selective depressant of cathepsin S.
in body
caCl
2
the AAA animal effectiveness models of inducing
Change as described below utilizes CaCl
2the AAA animal efficacy models of inducing the proteolytic enzyme S of research organization inhibitor to affect AAA (
j. Clin. Invest., 2002,110(5), 625～632).
Use is available from Taconic(Cambridge City, Indiana) the male 129SvEv mouse of wild-type (10 week age), be grouped as follows: 1 six groups of embodiment, 2 five groups of embodiment, every group containing 12 mouse.Respectively to group 1-5 administration vehicle solution---1% NATROSOL (Natvosol)/0.25% TWEEN 80(Polysorbate 80 of embodiment 1 and 2)/test compounds of 0.05% Antifoam-1510 (Dow Corning) and 1,3,10 or 30 mg/kg/vehicle solution, by every day twice per os raise by force administration 4 weeks.Introducing group 6(is in the research of embodiment 1) to set up baseline, wherein organize 6 and represent that sham operated rats (applies 0.9% salt solution to aorta and replaces CaCl
2, and with the vehicle medication).Give the first dosage the day before yesterday of operation (afternoon), the operation that morning gives the second dosage.The operation same day, not to animal give afternoon dosage.Performing the operation next day, twice medication every day (morning and afternoon) proceeded to 28 days.
Operation same day, animal 10 minutes and accept subcutaneous pain relieving (BUPRENEX, 0.1 mg/kg) in postoperative 3 hours in the preoperative.Make mouse anesthesia by sucking 2% isoflurane, and carry out laparotomy ventrotomy.By laterally regaining intestines by surgical retractors and intestines being stayed in abdominal cavity, and aorta abdominalis is exposed.Utilize microsurgical technique, will be from the Renal artery level aorta abdominalis to the ilium crotch and postcava and reticular tissue on every side separate.Once separate, by the concerned district of aorta abdominalis with being immersed in 0.25M CaCl
2premeasuring sterile cotton gauze parcel in the aqueous solution.In the sham-operation control animal, with 0.9% salt solution, replace CaCl
2.After 7 minutes, remove described gauze, apply second CaCl
2the gauze soaked (or the gauze crossed of 0.9% saline soak is for sham-operation animal).After second 7 minute period, remove described gauze, with 0.9% normal saline washing aorta, closed abdominal cavity.Allow animal get back to general residence, at this, by they independent stable breedings (house), and arbitrarily obtain standard rodent diet (Purina 2014) and water.
Medication is after 4 weeks as mentioned above, measure aorta lumen girth, area and the diameter with the aorta section of gauze parcel by ultrasonic (Biosound Ultrasound-7.5 MHz), and carry out statistical analysis with JMP 7 softwares (Cary, North Carolina).By measuring the aorta lumen girth (due to the irregular geometry associated with surveyed aorta section, the aorta lumen girth represents that more accurate aorta abdominalis measures in this case) the AAA reduction per-cent measured is shown in following table 1, and illustrates with mean value ± standard deviation.For embodiment 1, vehicle group and sham operated rats to be made comparisons, test compounds and vehicle are made comparisons.For embodiment 2, test compounds and vehicle are made comparisons.
AAA reduction per-cent (%) in table 2. body
| Group | Embodiment 1 | Embodiment 2 |
| Vehicle | 0±9 | 0±8 |
| 1 mg/kg | 58±10 | 11±7 |
| 3 mg/kg | 83±8 | 32±9 |
| 10 mg/kg | 87±8 | 43±9 |
| 30 mg/kg | 87±7 | 52±7 |
According to scheme as above basically, embodiment 1 and 2 compound reduce the aorta lumen girth in the dose-dependently mode, prove that thus some compound in the scope of the invention has reduced AAA.
p10 builds up test
Use is available from Taconic(Cambridge City, Indiana) the male C57B6 of wild-type or 129SvEv mouse (10 week age), be divided into four groups, every group containing 3 mouse.By per os, raise by force, respectively to group 1-4 administration vehicle solution-1 % NATROSOL (Natvosol)/0.25% TWEEN 80(Polysorbate 80)/0.05% Antifoam-1510(Dow Corning) and the test compounds of 3,10 or 30 mg/kg/vehicle solution.After 4 hours, from each mouse suction whole blood (300-500 μ L).Removing erythrocytic step carries out as follows: add 1 mL Flow Cytometry Lysing Solution (Santa Cruz Biotechnology, Inc.), keep under room temperature 10 minutes, and under 4000 rpm centrifugal 5 minutes, abandoning supernatant then.This step is repeated once, to remove red blood corpuscle fully.With 50 μ L CytoBuster
reagent (Novagen) suspends the PWBC spherolite again, and under superpower supersound process 5-10 second.Utilize BCA test determination protein concentration (
anal. Biochem.1988,175,231-237
).
Utilize western blotting to measure the p10 amount.Make sample (0.5 μ g/ μ L protein concentration) 96 ℃ of lower sex change 5 minutes, 20 μ L/ hole samples (10 μ g/ hole) are loaded on 4-12%NUPAGE NOVEX Bis-Tris Midi-gel (Invitrogen).With NUPAGE MES SDS running buffer (Invitrogen), make gel move 60 minutes under 120 V.Adopt NUPAGE transfering buffering liquid (Invitrogen) and 20% methyl alcohol (EMD), under 100 V, protein delivery to 0.2 μ m soluble cotton (BIO-RAD) is continued to 30 minutes.Rinse in short-term trace with PBS, and at room temperature with 10 mL, be enclosed in ODYSSEY sealing damping fluid (LI-COR Biosciences) 60 minutes.For p10, under 4 ℃, adopt the one-level antibody (the anti-CD74 antibody of the rat of 1 μ g/mL) (BD Bioscience) for mouse CD74 that blotting incubation is spent the night in the sealing damping fluid.For the tubulin contrast, adopt the anti-beta tubulin pAb(0.2 of rabbit μ g/mL under 4 ℃) (Abcam) blotting incubation is spent the night in the sealing damping fluid.Trace is washed 4 times with the lavation buffer solution (DPBS, available from HyClone) containing 0.01% Polysorbate20, and each 10 minutes.Then, at room temperature trace is hatched 60 minutes by secondary antibody.For p10, use the ALEXA FLUOR 680 mouse IgG(1:5000 of goat Chinese People's Anti-Japanese Military and Political College extent of dilution) (Invitrogen).For tubulin, use ALEXA FLUOR 680 goat anti-rabbit iggs (1:5000 extent of dilution) (Invitrogen).Again wash as mentioned above trace, be placed in PBS and scanned.
By in the upper scanning of ODYSSEY infrared thermoviewer (LI-COR Biosciences), catching image.P10 amount is analyzed with ODYSSEY software, and with the normalization method of tubulin amount.Data are carried out statistical analysis with JMP 7 softwares (Cary, North Carolina).Building up (multiple increase) with respect to vectorial relative p10 is shown in Table 3.Numeric representation is mean value ± standard deviation.
Relative p10 in table 3. body in PWBC builds up
| Group | Embodiment 1 | Embodiment 2 |
| Vehicle | 1.0±0.8 | 1.0±0.2 |
| 3 mg/kg | 2.1±0.5 | 1.1±0.7 |
| 10 mg/kg | 3.9±0.2 | 2.2±1.3 |
| 30 mg/kg | 4.6±1.0 | 4.6±1.2 |
According to such scheme, embodiment 1 and 2 compound increase the p10 in PWBC in the dose-dependently mode, have proved that some the compound blocking antigen in the scope of the invention is presented.
Claims (15)
1. formula (I) compound:
Or its pharmacologically acceptable salt,
Wherein,
Z is-CH
2-,-CH
2cH
2-,-OCH
2-,-CH
2cH
2cH
2-or-OCH
2cH
2-;
R
1h, F or Cl;
R
2h, methyl, ethyl, propyl group or sec.-propyl.
2. according to the compound or pharmaceutically acceptable salt thereof of claim 1, R wherein
1h or F.
3. according to the compound or pharmaceutically acceptable salt thereof of claim 1 or 2, R wherein
1f.
4. according to the compound or pharmaceutically acceptable salt thereof of any one of claim 1-3, R wherein
2methyl or ethyl.
5. according to the compound or pharmaceutically acceptable salt thereof of any one of claim 1-4, R wherein
2it is methyl.
6. according to the compound or pharmaceutically acceptable salt thereof of any one of claim 1-5, wherein Z is-CH
2cH
2-or-OCH
2-.
7. according to the compound or pharmaceutically acceptable salt thereof of claim 1, described compound has the following formula structure:
8. according to the compound or pharmaceutically acceptable salt thereof of claim 1, described compound has the following formula structure:
9. pharmaceutical composition, this pharmaceutical composition comprises according to the compound of any one of claim 1-8 and pharmaceutically acceptable diluent or carrier.
10. treat the method for abdominal aortic aneurysm, patch unstable, atherosclerosis, rheumatoid arthritis, psoriasis or lupus in the Mammals that needs it, the method comprises to the compound or pharmaceutically acceptable salt thereof of any one according to claim 1-8 of described Mammals drug treatment significant quantity.
11. treat the method for abdominal aortic aneurysm, patch unstable, atherosclerosis, rheumatoid arthritis, psoriasis or lupus in the Mammals that needs it, the method comprises to the pharmaceutical composition according to claim 9 of described Mammals drug treatment significant quantity.
12. the method for claim 10 or 11, wherein said Mammals is the people.
13., according to the compound or pharmaceutically acceptable salt thereof of any one of claim 1-8, it is used for the treatment of.
14., according to the compound or pharmaceutically acceptable salt thereof of any one of claim 1-8, it is used for the treatment of abdominal aortic aneurysm, patch unstable, atherosclerosis, rheumatoid arthritis, psoriasis or lupus.
15. the purposes of any one compound or pharmaceutically acceptable salt thereof required for protection of claim 1-8, it is for the preparation of the medicine for the treatment of abdominal aortic aneurysm, patch unstable, atherosclerosis, rheumatoid arthritis, psoriasis or lupus.
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| Application Number | Priority Date | Filing Date | Title |
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| US39442410P | 2010-10-19 | 2010-10-19 | |
| US61/394,424 | 2010-10-19 | ||
| PCT/US2011/056244 WO2012054315A1 (en) | 2010-10-19 | 2011-10-14 | Cathepsin s inhibitor compounds |
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| US (1) | US8227468B2 (en) |
| EP (1) | EP2630141A1 (en) |
| JP (1) | JP2013540154A (en) |
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| CN110831926A (en) * | 2017-04-27 | 2020-02-21 | 持田制药株式会社 | Novel tetralinyl urea derivatives |
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| WO2005039496A2 (en) * | 2003-10-21 | 2005-05-06 | Irm Llc | Inhibitors of cathepsin s |
| CN101671310A (en) * | 2004-08-17 | 2010-03-17 | 诺瓦提斯公司 | Compounds and compositions useful as cathepsin s inhibitors |
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| SE9703377D0 (en) | 1997-09-18 | 1997-09-18 | Astra Ab | New compounds |
| CN1298707C (en) | 2000-11-21 | 2007-02-07 | 沃泰克斯药物股份有限公司 | Imidazole and benzimiddzole caspase inhibitors and uses thereof |
| AU2002332541B2 (en) | 2001-09-21 | 2008-05-08 | Eli Lilly And Company | Muscarinic agonists |
| WO2008130322A1 (en) | 2007-04-23 | 2008-10-30 | Astrazeneca Ab | Novel 5-heterocyclyl-chromane derivatives for the treatment of pain |
-
2011
- 2011-10-07 TW TW100136576A patent/TWI402072B/en not_active IP Right Cessation
- 2011-10-11 AR ARP110103731A patent/AR083364A1/en unknown
- 2011-10-14 EP EP11776639.4A patent/EP2630141A1/en not_active Withdrawn
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- 2011-10-14 US US13/273,302 patent/US8227468B2/en not_active Expired - Fee Related
- 2011-10-14 CN CN2011800507006A patent/CN103153989A/en active Pending
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002040462A2 (en) * | 2000-11-17 | 2002-05-23 | Medivir Uk Limited | Cysteine protease inhibitors |
| WO2005039496A2 (en) * | 2003-10-21 | 2005-05-06 | Irm Llc | Inhibitors of cathepsin s |
| CN101671310A (en) * | 2004-08-17 | 2010-03-17 | 诺瓦提斯公司 | Compounds and compositions useful as cathepsin s inhibitors |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110831926A (en) * | 2017-04-27 | 2020-02-21 | 持田制药株式会社 | Novel tetralinyl urea derivatives |
| CN110831926B (en) * | 2017-04-27 | 2023-11-21 | 持田制药株式会社 | Tetrahydronaphtyl urea derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20130093120A (en) | 2013-08-21 |
| WO2012054315A1 (en) | 2012-04-26 |
| EP2630141A1 (en) | 2013-08-28 |
| MX2013004421A (en) | 2013-12-02 |
| AR083364A1 (en) | 2013-02-21 |
| US20120095020A1 (en) | 2012-04-19 |
| CA2816033A1 (en) | 2012-04-26 |
| TW201231053A (en) | 2012-08-01 |
| CA2816033C (en) | 2014-04-08 |
| US8227468B2 (en) | 2012-07-24 |
| BR112013009670A2 (en) | 2016-07-12 |
| TWI402072B (en) | 2013-07-21 |
| AU2011318316A1 (en) | 2013-05-02 |
| EA201370052A1 (en) | 2013-11-29 |
| JP2013540154A (en) | 2013-10-31 |
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